Coronary heart disease, the result of coronary atherosclerosis, is the leading cause of morbidity and mortality worldwide. Lipid lowering reduces the development of atherosclerosis and of cardiovascular events. The inhibitors of the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (statins) are the most effective and widely used lipid-lowering drugs for the prevention of cardiovascular events. Statins also exert endothelial protective, anti-inflammatory and antithrombotic actions, which are independent of serum cholesterol lowering. Although poor compliance is the commonest cause of statin discontinuation, nearly 1.5% of patients stop therapy because of adverse effects. Statin discontinuation has been associated with increases in thrombotic vascular events, and fatal or non-fatal myocardial infarction in subjects with advanced vascular disease, endothelial dysfunction in healthy normocholesterolemic men, and severe impairment in the production of nitric oxide, a vascular protective gas. In this proposal, we will investigate how statin withdrawal induces vascular dysfunction. Our hypothesis is that upon statin withdrawal, there is a period of time during which vascular protective mechanisms are inhibited and vasoconstrictive, growth-promoting and pro-inflammatory mechanisms are activated. During such a period there will be an increased risk for cardiovascular events. Our focus will be the effects of statin withdrawal on angiotensin II, a vasoconstrictor that promotes vascular growth and inflammation, through its action on AT1 receptors. Published evidence indicates that treatment with statins increases the synthesis and availability of nitric oxide, and reduces the synthesis of the AT1 receptors. Both effects are achieved through a similar mechanism; namely, inhibition of rho GTPases. Discontinuing statins has been shown to markedly increase the activity of rho GTPases, therefore it is expected that in addition to turning-off nitric oxide production (a well-known effect), it will simultaneously activate the synthesis of AT1 receptors (unknown). We propose that statin withdrawal induces marked upregulation of AT1 receptors due to increased synthesis, and that the AT1 receptors will be coupled and functional, leading to greater effects of angiotensin II. A combination of impaired nitric oxide production with increased AT1-receptor stimulation may explain the vascular dysfunction reported after statin withdrawal. To test our hypothesis AT1-receptor mRNA expression, AT1 receptor levels, AT1 receptor function (signaling and effects), and NO production and expression, will be quantitated in vascular endothelial and smooth muscle cells in culture, as well as in vivo in mouse aortas. Our study may provide the basis for preventive and corrective interventions to millions of people that are under statin treatment. [unreadable] [unreadable]